The present invention is related to new oral pharmaceutical dosage forms which comprise a proton pump inhibitor, i.e. a H+,K+-ATPase inhibitor. The new dosage forms are enteric coated formulations which provide a discontinuous pattern of two or more discrete release pulses of the H+,K+-ATPase inhibitor in the small and/or large intestines. The pulses are separated in time by from 0.5 and up to 12 hours, they are preferably separated by from 0.5 and up to 6 hours, and more preferably from 0.5 and up to 4 hours. Furthermore, the present invention refers to the manufacture of such pulsed delayed release pharmaceutical formulations, and their use in medicine.
Acid labile H+,K+-ATPase inhibitors also named as gastric proton pump inhibitors are for instance compounds known under the generic names omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Some of these compounds are disclosed in EP-A1-0005129, EP-A1-124495, WO 94/27988, EP-A1-174726, EP-A1-166287 and GB 2163747.
These pharmaceutical substances are useful for inhibiting gastric acid secretion in mammals including man by controlling gastric acid secretion at the final step of the acid secretory pathway and thus reduce basal and stimulated gastric acid secretion irrespective of stimulus. In a more general sense, they may be used for prevention and treatment of gastric-acid related diseases in mammals and man, including e.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrome. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, and in patients with symptomatic gastro-oesophageal reflux disease (GORD). They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre-and post-operatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, they may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these.
Therapeutic control of gastric acid secretion is fundamental in all these disease, but the degree and duration of acid inhibition required for optimal clinical effect is not fully understood.
It has been proposed by the Applicant in WO97/48380, (published Dec. 24, 1997 i.e. after the priority date of the instant application,) that an administration regimen that gives blood plasma levels extending from 2-12 hours (by any of several means) will result in a larger fraction of proton pumps being inhibited. Thus, an extended blood plasma level 15 should result in more effective inhibition of acid secretion resulting in improved efficacy in GORD, more rapid healing of gastric ulcer and improved eradication of H. Pylori. The present invention provides pharmaceutically dosage forms which achieve such extended plasma levels by releasing the drug in two or more separate pulses.
A pharmaceutical dosage form of omeprazole or any other proton pump inhibitor is best protected from contact with acidic gastric juice by an enteric coating layer. In U.S. Pat. Nos. 4,786,505 and 4,853,230 such enteric coated preparations are described. These preparations have a core comprising an alkaline salt of the drug or a core comprising the drug together with an alkaline reacting compound. The core is coated with a water soluble or in water rapidly disintegrating separating layer and then with an enteric coating layer. WO 96/01623 and WO 96/01624 describe tableted dosage forms of omeprazole and other proton pump inhibitors, wherein enteric coating layered pellets are compressed into a multiple unit tableted dosage form. It is essential in these tableted formulations that the enteric coating layer can withstand the compression forces. None of these by the Applicant previously described formulations gave a dissolution of two or more pulses separated in time, i.e. in the meaning of pulsed release of the proton pump inhibitor which resulted in an extended blood plasma profile.
There are different technologies and pharmaceutical formulations described in the prior art which aim at a delayed release of an administered drug. Such pharmaceutical formulations are for instance formulations providing different lag times, constructions based on osmotic differences, slow-eroding/dissolving layers, time controlled explosion systems or any combinations thereof. In the following discussion some of these principles are described.
Gazzaniga et al (Proceed. 12th Pharm. Int. Techn. Conf., 1993, 1, 400-8.) described tablets which were spray-coated or press-coated with HPMC layers to obtain delayed release preparations of ketoprofen or verapamil. The HPMC layer may also contain an insoluble filler. Gazzaniga et al have also described press-coated tablets containing antipyrine with HPMC layers to obtain delayed release, having an outer enteric coating comprising Eudragit L30D applied thereon. (Proc. Inter. Symp. Control. Rel. Bioact. Mater. 1996, 23, 571-2.)
EP-A1-0629398 describes a dosage form comprising a drug and an organic acid in a core surrounded by a film that controls the start of release, and further covered by an enteric coating layer. This dosage form is not suitable for substances that are sensitive to acidic degradation as the core comprises an organic acid.
Osmotic systems are described by Fox (xe2x80x9cColon-Targeted Osmotic System for Oral delivery of Peptides and Proteinsxe2x80x9d, In; Oral Delivery of Proteins, Peptides and other Biopharmaceutical Agents; Proceedings Technology Management Group, Wakefield, Mass., USA, September 1991). A colon release system, OROS-CT, is used to obtain delayed extended release after a lag time. The dosage form had an enteric coating which dissolved in the small intestines, the drug release started after a desired lag time and the release was maintained during some hours.
EP 0384642 and EP 0384646 (as well as Pharm. J., Jul. 27, 1991 pp.137-9) introduced the PULSINCAP(copyright) dosage form both for enteric coated system and non-enteric coated system. The system comprises a capsule composed of a water insoluble body and a water soluble cap. The drug formulation was contained within the capsule body and sealed within this region by means of a hydrogel plug.
Conte et al (Drug Development and Industrial Pharmacy, 1989, vol 15, pp. 2583-96) described a three-layer tablet giving a double pulse system suitable for ibuprofen. The first layer contained a rapidly releasing formulation, and was separated from the layer comprising the second dose by a swellable polymeric barrier layer. The second dose was coated with an impermeable film of ethyl cellulose. This construction releases the drug in an acidic medium.
A dosage form for diltiazem was described in U.S. Pat. No. 5,567,441 comprising a mixture of one fraction of enteric coated pellets with slow release and another fraction of delayed pulse release membrane coated pellets. The latter fraction of pellets were not enteric coated. Such a dosage form will not be suitable for acidic sensitive drugs such as omeprazole or the like. There are two newly published patent applications which propose controlled release formulations comprising a proton pump inhibitor, i.e. in WO 97/02020 a dosage form for pantoprazole in combination with an antibacterial substance is proposed. At least a part of the pantoprazole dose shall be in slow-release form with a continuous release of pantoprazole over time. The preparation has one intermediate layer which will remain intact as a layer and is releasing the dose of pantoprazole continuously so as a pantoprazole plasma level persists as long as possible. WO 97/02021 discusses a very similar dosage form of a reversible proton pump inhibitor in combination with an antibacterial substance.